Efficient Synthesis of [2-15N]Guanosine and 2′-Deoxy[2′-15N]Guanosine Derivatives Using N-(tert-Butyldimethylsilyl)[15N]Phthalimide as a 15N-Labeling Reagent

Nucleophilic aromatic substitution of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-fluoro-9 H-purine with N-(tert-butyldimethylsilyl)[ ¹⁵ N]phthalimide in the presence of a catalytic amount of CsF at room temperature in DMF efficiently afforded the 6-chloro-2-[ ¹⁵ N]phthalimidopurine derivative, which was subsequently converted to the [2-¹⁵N]guanosine derivative was also efficiently synthesized through a similar procedure.     

An Efficient Method for the Synthesis of [4–15N]Cytidine, 2′-Deoxy[4–15N]Cytidine, [6–15N]adenosine,and 2′-Deoxy [6–15N]adenosine Derivatives

Abstract

Nucleophilic substitution reactions of 4-azolyl-1 β-P-D-ribofuranosylpyrimidin-2(1H)-one and 6-azolyl-9-β-D-ribofuranosyl-9H-purine derivatives, which were converted from uridine and inosine, with [¹⁵N]phthalimide in the presence of triethylamine or DBU gave N ⁴-phthaloyl[4-¹⁵N]cytidine and N ⁶-phthaloyl[6-¹⁵N]- adenosine derivatives, respectively, in high yields. Similar reactions of those azolyl derivatives with succinimide afforded N ⁴-succinylcytidine and N ⁶-succinyladenosine derivatives in high yields. The corresponding 2′-deoxyribonucleosides were also synthesized efficiently through the same procedure.

     

The biodistribution of [75Se]bis-[β-(N,N,N-trimethylamino)ethyl]selenide diiodide in adult guinea pigs

The biodistribution of [⁷⁵Se]BISTAES was studied in guinea pigs. A higher concentration of radioactivity was observed in articular cartilage than in other tissues or organs. A minimal amount of radioactivity was found in the blood, muscle and bone. The compound was excreted rapidly in urine. The target to background ratios were encouraging. [⁷⁵Se]BISTAES has potential as an articular cartilage imaging agent and further studies in osteoarthritic animals are merited.     

[B2-Lys]-胰岛素的制备与性质

本文报道了用化学半合成途径从天然猪胰岛素制备[B2-Lys]-胰岛素的过程。人胎盘细胞膜胰岛素受体结合试验表明:[B2-Lys]-胰岛素的受体结合能力只有天然胰岛素的80％,降兔血糖作用与时间关系的结果表明它没有长效作用。本文还对这些结果进行了讨论。     

Facile preparation of optically pure [α-2H]-α-amino acids

Summary Racemic [-²H]--amino acids were prepared by heating the corresponding amino acids (Phe, nor-Leu and Dopa) with 0.05 equivalents of benzaldehyde in deuterated-acetic acid. Based on¹H-nmr measurement, the isotopic purities of these racemized [-²H]--amino acids were found to be higher than 99.5%. Methylation of these isotope-labelled amino acids was achieved in methanol/thionyl chloride without affecting isotopic purity. Optically pure [-²H]--amino acids were obtained in high yield with high enantiomeric excess via alcalase catalysed resolution.     

Synthesis and radiopharmacological investigation of 3-[4′-[18F]fluorobenzylidene]indolin-2-one as possible tyrosine kinase inhibitor

The radiosynthesis and radiopharmacological evaluation of 3-[4′-[¹⁸F]fluorobenzylidene]indolin-2-one, a derivative of tyrosine kinase inhibitor SU5416, is described. The radiosynthesis was accomplished by Knoevenagel condensation of 4-[¹⁸F]fluorobenzaldehyde with oxindole in a remotely controlled synthesis module. The reaction conditions were optimized through screening the influence of different bases on the radiochemical yield. The radiotracer was obtained after a two-step labelling procedure in 4% decay-corrected radiochemical yield at a specific activity of 48–61 GBq/μmol within 90 min. The radiochemical purity after semi-preparative HPLC purification exceeded 98%.The biodistribution was studied in Wistar rats. After distribution the radiotracer was rapidly accumulated in the adrenals, liver and kidneys, however, it was cleared from these and the most other organs. Only the adipose tissue remained the activity over 60 min. Unexpected high transient uptake was observed in the brain, pancreas, heart and lung. The fast clearance of 3-[4′-[¹⁸F]fluorobenzylidene]indolin-2-one was caused by excretion, approximately one half each was renal and biliary excreted and the other part cleared by metabolic processes. In arterial blood plasma two more polar metabolites were found by radio-HPLC. After 20 min post-injection, only 12% of intact radiotracer has been detected. Consequently, in small animal PET studies with FaDu tumour bearing mice no specific uptake in the tumours could be observed.     

[15N,1H]/[13C,1H]-TROSY for simultaneous detection of backbone 15N–1H, aromatic 13C–1H and side-chain 15N–1H2 correlations in large proteins

This paper describes a [¹⁵N,¹H]/[¹³C,¹H]-TROSY experiment for the simultaneous acquisition of the heteronuclear chemical shift correlations of backbone amide ¹⁵N–¹H groups, side chain ¹⁵N–¹H₂ groups and aromatic ¹³C–¹H groups in otherwise highly deuterated proteins. The ¹⁵N–¹H and ¹³C–¹H correlations are extracted from two subspectra of the same data set, thus preventing possible spectral overlap of aromatic and amide protons in the ¹H dimension. The side-chain ¹⁵N–¹H₂ groups, which are suppressed in conventional [¹⁵N,¹H)-TROSY, are observed with high sensitivity in the ¹⁵N–¹H subspectrum. [¹⁵N,¹H]/[¹³C,¹H]-TROSY was used as the heteronuclear correlation block in a 3D [¹H,¹H]-NOESY-[¹⁵N,¹H]/[¹³C,¹H]-TROSY experiment with the membrane protein OmpA reconstituted in detergent micelles of molecular weight 80000 Da, which enabled the detection of numerous NOEs between backbone amide protons and both aromatic protons and side chain ¹⁵N–¹H₂ groups.     

Synthesis of novel spiro[pyrazolo[4,3-d]pyrimidinones and spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-diones and their evaluation for anticancer activity

An efficient and novel method for the preparation of spiro[pyrazolo[4,3-d]pyrimidin]-7′(1′H)-ones by the condensation of 4-amino-1-methyl-3-propylpyrazole-5-carboxamide with ketones under mild conditions using catalytic InCl₃ was reported. This method has been extended for the synthesis of novel spiro[benzo[4,5]thieno[2,3-d]pyrimidine-2,3′-indoline]-2′,4(3H)-dione which are having potential applications in medicinal chemistry. All the synthesized compounds were evaluated for their anti-proliferative properties in vitro against cancer cell lines and several compounds were found to be active. Further in vitro studies revealed that inhibition of sirtuins could be the possible mechanism of action of these molecules.     

Synthesis of Pyrrolo[2′,3′:4,5]Furo[3,2-c]Pyridine-2-Carboxylic Acids

1H-Pyrrolo[2′,3′:4,5]furo[3,2-c]pyridine-2-carboxylic acid (6a) and its 1-methyl (6b) and 1-benzyl (6c) derivatives were synthesized. 3-(5-Methoxycarbonyl-4H-furo[3,2-b]-pyrrole-2-yl)propenoic acid (1) was converted to the corresponding azide 2, which in turn was cyclized to give 3 by heating in diphenylether. The pyridone 3 obtained was aromatized with phosphorus oxychloride, then reduced with zinc in acetic acid to give methyl 1H-pyrrolo[2′,3′:4,5]furo[3,2-c]pyridine-2-carboxylate (5), which by hydrolysis gave the corresponding carboxylic acid 6a.     

Highly Diastereoselective Synthesis of (2′S)-[2′-2H]-2′-Deoxyribonucleosides from the Corresponding Ribonucleosides

Abstract

The four (2′S)-[2′-²H]-2′-deoxynucleosides (>90 atom % ²H), were synthesized from the corresponding ribonucleosides involving six steps of reactions, i.e., oxidation of their 2′-hydroxyl group, stereoselective reductive deuteration of the resulting 2′-ketonucleoside intermediates with NaB²H₄ in EtOH-H₂O or EtOH, triflation, bromination with LiBr, highly stereoselective Bu₃SnH-Et₃B reduction of the resulting bromide, and, finally, unmasking.     

[~3H]2-脱氧葡萄糖定量研究方法的介绍

2-脱氧葡萄糖(2-DG)方法是一种新的形态与功能结合的神经科学研究方法。我们在现有条件下对此方法的应用做了一些研究。在实验中,我们采用了股静脉注射[~3H]标记的2-DG,测定血糖、血液中放射性物质含量及用显微分光光度计测定放射自显影片光密度的方法,并采用 Sokoloff 的计算公式计算各脑区的葡萄糖代谢率。     

A Synthesis of the Potent A2 Selective Adenosine Agonist N6-[2-(3,5-Dimethoxyphenyl)-2-(2-Methylphenyl)Ethyl]Adenosine,and Its 5′-N-Ethyl Ribofuranuronamide Derivative

Abstract

A detailed experimental procedure for the synthesis and resolution of 2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethylamine, and its conversion into the titled adenosine reference agonists is given.     

Enantioselective light switch effect of Δ- and Λ-[Ru(phenanthroline)2 dipyrido[3,2-a:2′, 3′-c]phenazine]2+ bound to G-quadruplex DNA

The interaction of Δ- and Λ-[Ru(phen)₂DPPZ]²⁺ (DPPZ = dipyrido[3,2-a:2′, 3′-c]phenazine, phen = phenanthroline) with a G-quadruplex formed from 5′-G₂T₂G₂TGTG₂T₂G_2–3′(15-mer) was investigated. The well-known enhancement of luminescence intensity (the ‘light-switch’ effect) was observed for the [Ru(phen)₂DPPZ]²⁺ complexes upon formation of an adduct with the G-quadruplex. The emission intensity of the G-quadruplex-bound Λ-isomer was 3-fold larger than that of the Δ-isomer when bound to the G-quadruplex, which is opposite of the result observed in the case of double stranded DNA (dsDNA); the light switch effect is larger for the dsDNA-bound Δ-isomer. In the job plot of the G-quadruplex with Δ- and Λ-[Ru(phen)₂DPPZ]²⁺, a major inflection point for the two isomers was observed at x ≈ .65, which suggests a binding stoichiometry of 2:1 for both enantiomers. When the G base at the 8th position was replaced with 6-methyl isoxanthopterin (6MI), a fluorescent guanine analog, the excited energy of 6-MI transferred to bound Δ- or Λ-[Ru(phen)₂DPPZ]²⁺, which suggests that at least a part of both Ru(II) enantiomers is close to or in contact with the diagonal loop of the G-quadruplex. A luminescence quenching experiment using [Fe(CN)₆]^4- for the G-quadruplex-bound Ru(II) complex revealed downward bending curves for both enantiomers in the Stern–Volmer plot, which suggests the presence of Ru(II) complexes that are both accessible and inaccessible to the quencher and may be related to the 2:1 binding stoichiometry.     

Analysis of [2H7]methionine, [2H4]methionine,methionine, [2H4]homocysteine and homocysteine in plasma by gas chromatography–mass spectrometry to follow the fate of administered [2H7]methionine

Homocysteine plays a key role in several pathophysiological conditions. To assess the methionine–homocysteine kinetics by stable isotope methodology, we developed a simultaneous quantification method of [²H₇]methionine, [²H₄]methionine, methionine, [²H₄]homocysteine and homocysteine in rat plasma by gas chromatography–mass spectrometry (GC–MS). [¹³C]Methionine and [¹³C]homocysteine were used as analytical internal standards to account for losses associated with the extraction, derivatization and chromatography. For labeled and non-labeled homocysteine measurements, disulfide bonds between homocysteine and other thiols or proteins were reduced by dithiothreitol. The reduced homocysteine and methionine species were purified by cation-exchange chromatography and derivatized with isobutyl chlorocarbonate in water–ethanol–pyridine. Quantification was carried out by selected ion monitoring of the molecular-related ions of N(O,S)-isobutyloxycarbonyl ethyl ester derivatives on the chemical ionization mode. The intra- and inter-day precision of the assay was less than 6% for all labeled and non-labeled methionine and homocysteine species. The method is sensitive enough to determine pharmacokinetics of labeled methionine and homocysteine.     

Synthesis of [1-[2′,5′-bis-O-(t-Butyldimethylsilyl)-β- L-ribofuranosyl] thymine]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (L-TSAO-T)

Abstract

Derivatives of TSAO-T based upon pentofuranose sugars with the L-configuration have been prepared and evaluated as inhibitors of HIV-1 induced cytopathicity.     

Syntheses and highly enantioselective fluorescent recognition of α-aminocarboxylic acid anions using chiral oxacalix[2]arene[2]bisbinaphthes

The triazine-based bisbinaphthyl crown ethers oxacalix[2]arene[2]bisbinaphthes R-1, R-2, R-3 and S-1, S-2, S-3 were synthesized. The interactions of these compounds with various α-aminocarboxylic acid anions were studied. The crown ethers were found to carry out highly enantioselective fluorescent recognition of α-aminocarboxylic acid anions. It is observed that within a certain concentration range, one enantiomer of the chiral α-aminocarboxylic acid anions can increase the fluorescence intensity of the crown ethers by fivefold to sixfold, whereas the other enantiomer scarcely enhances the fluorescence. Such unusually high enantioselective responses make these crown ethers very attractive as fluorescent sensors in determining the enantiomeric composition of α-aminocarboxylic acid anions.     

Synthesis of 1α-[2-H]Hydroxyvitamin D3

1α-[2-³H]Hydroxyvitamin D₃ was synthesized chemically. The preparation was radiochemically pure and had a high enough specific activity (4.2 Ci/mmol) to permit experiments using 62.5 pmol/rat. This preparation had as much effect as synthetic 1α-hydroxyvitamin D₃ in increasing the serum Ca level of vitamin D-deficient rats.     

L2[o,r2]上的人口算子

用LZ〔0,:。〕表示通常意义下的Hilbert空间.在空间L“〔0,1。〕中,人口发展算子A“2’定义如下:定义域。‘A,={。‘·,卜‘·,dP(了) dr一“(r)p(,)〔LZ〔o,:,〕;p(o)_。f犷,,_,.,、:,_、*,_、J_1、*‘_、二。,,、‘,*、‘_、__dp(:)=夕l无(r)h(了)户(,)d了卜对p(1)〔D(A),(AP)(7)=一丝书井三 rJ九一’一“一’J‘一‘一’dT一“(r)P(犷),其中,1。为社会中人能活到的最大年龄,〔;,,12〕为妇女育龄区间,h(1)表示生育模式,k(下)表示女性比例函数,那(犷)表示相对死亡率,口>o为妇女总和生育率.拼(r),k(了),h(了)满足下面条件(I).召(,),…     

Chelator-induced enhancement of 67Ga tumour imaging: Comparison of desferrioxamine with N,N′-ethylene-bis[2-hydroxy-5-carboxyphenylglycine]

Intravenous injection of the gallium chelating agents, N,N′-ethylene bis[2-hydroxy-5-carboxyphenylglycine], (COOH-EHPG), or desferrioxamine (DFO) after gallium-67 (⁶⁷Ga) injection, improved tumour/non-tumour tissue uptake ratios in mice bearing the EMT-6 sarcoma. Six hours post injection of gallium and 2 h post chelator, COOH-EHPG enhanced the tumour/blood ratios by an order of magnitude compared to untreated controls, whereas DFO increased the ratios three-fold. Twenty two hours post gallium and 2 h post chelator, the increases in ratios compared to controls were seven-fold for COOH-EHPG and two-fold for DFO. The study thus demonstrated the superior ability of COOH-EHPG for the enhancement of ⁶⁷Ga tumour/blood ratios compared with DFO.